Heterocyclic derivatives, preparation and therapeutic use thereof

ABSTRACT

The invention concerns compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     Wherein X, Y, R 1 , R 2 , R 3  and R 4  are as described herein. The invention also concerns a method for preparing same and the therapeutic use thereof.

This application is a continuation of International application No. PCT/FR2006/002,695, filed Dec. 11, 2006, which is incorporated herein by reference in its entirety; which claims the benefit of priority of French Patent Application No. 05/12,719, filed Dec. 12, 2005.

The present invention relates to heterocyclic derivatives, to their preparation and to their therapeutic use.

Diaryloxazole carboxamide derivatives are described as modulators of cannabinoid receptors in patent application WO 2005/080 357 and in Bioorg. Med. Chem. Lett., 2005, 15, p.1441; diarylthiazole carboxamide derivatives are described in patent applications WO 2003/078 413 and WO 2004/058 255 and in J. Med. Chem., 2005, 48, p.1823.

Patent application WO 2006/074 445 describes various heterocyclic compounds, especially thiazole and oxazole derivatives, as having activity on the cannabinoid CB₁ and CB₂ receptors.

Novel heterocyclic derivatives that have antagonist properties on the cannabinoid CB1 receptors have now been found.

One subject of the present invention is compounds corresponding to the formula:

in which:

-   -   X represents a group     -   Y represents an oxygen atom or a sulfur atom;     -   R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group;     -   R₂ represents:         -   a (C₁-C₇)alkyl;         -   a C₃-C₁₂ non-aromatic carbocyclic radical, which is             unsubstituted or substituted one or more times with a             (C₁-C₄)alkyl;         -   a methyl substituted with a C₃-C₁₂ non-aromatic carbocyclic             radical that is unsubstituted or substituted one or more             times on the carbocycle with a (C₁-C₄)alkyl;         -   a phenyl, which is unsubstituted or substituted one or more             times with substituents independently chosen from a halogen             atom, a (C₁-C₄)alkyl, a hydroxyl, a (C₁-C₄)alkoxy, a cyano,             a trifluoromethyl group, a trifluoromethoxy group; or from a             phenyl, phenoxy, pyrrolyl, imidazolyl, pyridyl or pyrazolyl             radical, the said radicals being unsubstituted or             substituted one or more times with a (C₁-C₄)alkyl;     -   a phenoxymethyl, which is unsubstituted on the methyl or         substituted on the methyl with one or two (C₁-C₄)alkyl groups,         and unsubstituted on the phenyl or substituted on the phenyl         with one or more substituents independently chosen from a         halogen atom, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a trifluoromethyl         group and a trifluoromethoxy group;         -   a benzyl, which is unsubstituted or substituted one or more             times on the phenyl with substituents independently chosen             from a halogen atom, a cyano, a (C₁-C₄)alkyl, a             (C₁-C₄)alkoxy, a trifluoromethyl group and a             trifluoromethoxy group; or α-substituted with one or two             identical or different groups chosen from a (C₁-C₄)alkyl and             a (C₃-C₇)cycloalkyl;         -   a benzhydryl or a benzhydrylmethyl group;         -   a 1,2,3,4-tetrahydronaphthyl, which is unsubstituted or             substituted one or more times with a (C₁-C₄)alkyl;         -   a pyrrolyl, imidazolyl, pyridyl, pyrazolyl, furyl or thienyl             radical, the said radicals being unsubstituted or             substituted with one or more substituents independently             chosen from a halogen atom, a (C₁-C₄)alkyl and a             trifluoromethyl group;         -   an indolyl, which is unsubstituted or substituted one or             more times with substituents independently chosen from a             halogen atom and a (C₁-C₄)alkyl;         -   a benzofuryl, which is unsubstituted or substituted one or             more times with substituents independently chosen from a             halogen atom and a (C₁-C₄)alkyl;     -   R₃ represents a phenyl, which is unsubstituted or substituted         one or more times with substituents independently chosen from a         halogen atom, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a trifluoromethyl         or trifluoromethoxy group and a group S(O)_(n)Alk;     -   R₄ represents a phenyl, which is unsubstituted or substituted         one or more times with substituents independently chosen from a         halogen atom, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a trifluoromethyl         or trifluoromethoxy group, a trifluoromethoxy group and a group         S(O)_(n)Alk;     -   R₅ represents a hydrogen atom or a (C₁-C₄)alkyl;     -   n represents 0, 1 or 2;     -   Alk represents a (C₁-C₄)alkyl; on condition that when X         represents a group —CO— or —CONR₅—, R₂ is other than:         -   a C₄-C₇ non-aromatic carbocyclic radical, which is             unsubstituted or substituted one or more times with a             (C₁-C₄)alkyl;         -   a phenyl, which is unsubstituted or substituted one or more             times with substituents independently chosen from a halogen             atom, a (C₁-C₄)alkyl, a hydroxyl, a (C₁-C₄)alkoxy, a cyano             and a trifluoromethyl group; or from a 1-pyrrolyl or             1-pyrazoyl radical;         -   a 1,2,3,4-tetranaphthalene, which is unsubstituted or             substituted one or more times with a (C₁-C₄)alkyl;         -   a pyrrolyl, imidazolyl, pyridyl, pyrazolyl, furyl or thienyl             radical, the said radicals being unsubstituted or             substituted with one or more substituents independently             chosen from a halogen atom, a (C₁-C₄)alkyl and a             trifluoromethyl group;         -   an indolyl, which is unsubstituted or substituted one or             more times with substituents independently chosen from a             halogen atom and a (C₁-C₄)alkyl;         -   a benzofuryl, which is unsubstituted or substituted one or             more times with substituents independently chosen from a             halogen atom and a (C₁-C₄)alkyl.

The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of hydrates or solvates, i.e. in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the invention.

The term “halogen atom” means a bromine, chlorine, fluorine or iodine atom.

The terms “(C₁-C₄)alkyl” and “(C₁-C₇)alkyl” mean, respectively, a linear or branched alkyl radical of 1 to 4 carbon atoms or, respectively, of 1 to 7 carbon atoms, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl or heptyl radical.

The term “(C₁-C₄)alkoxy” means a linear or branched alkoxy radical of 1 to 4 carbon atoms such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy radical.

The term “(C₃-C₁₂) non-aromatic carbocyclic radical” means: a monocyclic radical or a fused or bridged bicyclic or tricyclic radical; the term “monocyclic radical” means a cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, the cyclopentyl, cyclohexyl and cycloheptyl radicals being preferred; the term “fused or bridged bicyclic or tricyclic radical” means, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl or adamantyl.

Among the compounds of formula (I) that are subjects of the invention, mention is made of the oxazoles of formula (I) in which —Y— represents an oxygen atom, and the thiazoles of formula (I) in which —Y— represents a sulfur atom.

Among the compounds of formula (I) that are subjects of the invention, mention is made of:

-   -   the compounds of formula (IA) in which —X— represents a group         —CO— and the substituents R₁ to R₄ are as defined for the         compounds of formula (I);     -   the compounds of formula (IB) in which —X— represents a group         —SO₂— and the substituents R₁ to R₄ are as defined for the         compounds of formula (I);     -   the compounds of formula (IC) in which —X— represents a group         —CON(R₅)— and the substituents R₁ to R₅ are as defined for the         compounds of formula (I);     -   the compounds of formula (ID) in which —X— represents a group         —CSN(R₅)— and the substituents R₁ to R₅ are as defined for the         compounds of formula (I).

More particularly, mention is made of:

-   -   the oxazoles of formula (IA) in which Y represents an oxygen         atom, X represents a group —CO— and the substituents R₁ to R₄         are as defined for (I);     -   the thiazoles of formula (IA) in which Y represents a sulfur         atom, X represents a group —CO— and the substituents R₁ to R₄         are as defined for (I);     -   the oxazoles of formula (IB) in which Y represents a sulfur         atom, X represents a group —SO₂— and the substituents R₁ to R₄         are as defined for (I);     -   the thiazoles of formula (IB) in which Y represents a sulfur         atom, X represents a group —SO₂— and the substituents R₁ to R₄         are as defined for (I);     -   the oxazoles of formula (IC) in which Y represents an oxygen         atom, X represents a group —CON(R₅)— and the substituents R₁ to         R₅ are as defined for (I);     -   the thiazoles of formula (IC) in which Y represents a sulfur         atom, X represents a group —CON(R₅)— and the substituents R₁ to         R₅ are as defined for (I);     -   the oxazoles of formula (ID) in which Y represents an oxygen         atom, X represents a group —CSN(R₅)— and the substituents R₁ to         R₅ are as defined for (I);     -   the thiazoles of formula (IE) in which Y represents a sulfur         atom, X represents a group —CSN(R₅)— and the substituents R₁ to         R₅ are as defined for (I).

Among the compounds that are subjects of the invention, the compounds that are preferred are those of formula (I) in which:

-   -   R₁ represents a hydrogen atom;     -   R₂ has one of the values defined for (I);     -   R₃ and R₄ represent a 2,4-dichlorophenyl and a 4-chlorophenyl, a         2-chlorophenyl and a 4-chlorophenyl, or a 2,4-dichlorophenyl and         a 4-methoxyphenyl;

and also the hydrates or solvates thereof.

The compounds that are most particularly preferred are those of formula (I) in which the substituents R₁, R₃ and R₄ are as defined above and R₂ represents a group chosen from:

-   -   a (C₁-C₇)alkyl;     -   a benzhydrylmethyl group;

and also the hydrates or solvates thereof.

Compounds that are also preferred are those of formulae (IB) and (ID) in which the substituents R₁, R₃ and R₄ are as defined above and R₂ represents a group chosen from:

-   -   -   a phenyl substituted one or more times with substituents             independently chosen from a halogen atom, a (C₁-C₄)alkyl and             a trifluoromethyl group;         -   a pyrazolyl radical, which is unsubstituted or substituted             with a (C₁-C₄)alkyl;         -   a 2-indolyl radical, which is unsubstituted or substituted             with a (C₁-C₄)alkyl;

and also the hydrates or solvates thereof.

In accordance with the invention, the compounds of formula (I) may be prepared according to a process that is characterized in that:

a compound of formula:

in which R₁, R₃ and R₄ are as defined for a compound of formula (I) is treated:

-   -   either with an acid or a functional derivative of this acid of         formula:

HOOC—R₂   (III)

in which R₂ is as defined for a compound of formula (IA), when a compound of formula (IA) needs to be prepared, in which —X— represents a group —CO—;

-   -   or with a sulfonyl halide of formula:

Hal-SO₂—R₂   (IV)

in which R₂ is as defined for a compound of formula (I) and Hal represents a halogen atom, preferably chlorine, when a compound of formula (IB) needs to be prepared, in which —X— represents a group —SO_(2—;)

-   -   or with a haloformate of formula:

HalCOOAr   (V)

in which Hal represents a halogen atom and Ar represents a phenyl or a 4-nitrophenyl, to obtain an intermediate compound of formula:

in which R₁, R₃ and R₄ are as defined for a compound of formula (I), which is then reacted with an amine of formula:

HN(R₅)R₂   (VII)

in which R₂ and R₅ are as defined for a compound of formula (I), when a compound of formula (IC) needs to be prepared, in which —X— represents a group

-   -   —CON(R₅)—;     -   or with an isothiocyanate R₂N═C═S (VIII), when a compound of         formula (ID) needs to be prepared, in which —X— represents a         group —CSNH—.

Where appropriate, a compound of formula (IC) or (ID) in which R₅ represents a (C₁-C₄)alkyl group may be prepared via an alkylation reaction on the corresponding compound of formula (I) in which R₅ represents a hydrogen atom.

Optionally, the compound of formula (I) is converted into an acid-addition salt thereof.

When a compound of formula (II) is treated with the acid of formula (III) itself, the process is performed in the presence of a coupling agent used in peptide chemistry, such as 1,3-dicyclohexylcarbodiimide (DCC) or benzotriazol-1-yloxytris(dimethylamino)phosphonium (BOP) hexafluorophosphate or benzotriazol-1-yloxytris(pyrrolidino)phosphonium (PyBOP) hexafluorophosphate or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), in the presence of a base such as triethylamine, N,N-diisopropylethylamine or 4-dimethylaminopyridine, in a solvent such as dichloromethane, dichloroethane, N,N-dimethylformamide or tetrahydrofuran, at a temperature of between −10° C. and the reflux temperature of the solvent.

As functional derivative of the acid (III), it is possible to use the acid chloride, the anhydride, a mixed anhydride, a C₁-C₄ alkyl ester in which the alkyl is straight or branched, and an activated ester, for example p-nitrophenyl ester.

Thus, in the process according to the invention, the acid chloride obtained by reacting thionyl chloride or oxalyl chloride with the acid of formula (III) can also be reacted with the compound of formula (II), in a solvent, such as a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform), an ether (for example tetrahydrofuran or dioxane) or an amide (for example N,N-dimethylformamide), under an inert atmosphere, at a temperature of between 0° C. and room temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.

One variant consists in preparing the mixed anhydride of the acid of formula (III) by reacting ethyl chloroformate with the acid of formula (III), in the presence of a base such as triethylamine, and in reacting it with the compound of formula (II), in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.

When a compound of formula (II) is treated with a sulfonyl halide of formula (IV), the process is performed in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran and at a temperature of between room temperature and the reflux temperature of the solvent.

When a compound of formula (II) is treated with a haloformate of formula (V), the process is performed in the presence of a base such as triethylamine, in a solvent such as dichloromethane and at a temperature of between 0° C. and room temperature. The intermediate compound of formula (VI) thus obtained is then reacted with an amine of formula (VII), in a solvent such as dichloromethane, in the presence of a base such as triethylamine and at a temperature of between 0° C. and the reflux temperature of the solvent.

According to one variant of the process, the compounds of formula (IC) in which —X— represents a group —CON(R₅)— in which R₅═H, may be prepared by reacting a compound of formula (II) with an isocyanate of formula R₂—N═C═O (VIII), in the presence of a base such as triethylamine, in a solvent such as dichloromethane and at a temperature of between room temperature and the reflux temperature of the solvent.

According to another variant of the process, the compounds of formula (IC) in which —X— represents a group —CON(R₅)— may be prepared by reacting a compound of formula (II) with a compound of formula ClCON(R₅)R₂ (IX) in the presence of a base such as triethylamine, in a solvent such as dichloromethane and at a temperature of between 0° C. and room temperature.

The compounds of formula (IA), (IB), (IC with R₅≠H), (ID with R₅≠H) in which R₁ represents a (C₁-C₃)alkyl may also be prepared from the corresponding compounds of formula (I) in which R₁ represents a hydrogen atom, via a method chosen from the methods known to those skilled in the art, such as alkylation with an alkyl halide.

The compounds of formula (I) thus obtained may be subsequently separated from the reaction medium and purified according to the standard methods, for example by crystallization or chromatography.

The compounds of formula (II) may be prepared according to the following reaction scheme:

The ester of formula (IX) is prepared according to the process described in International patent application WO 2005/080 357 or WO 2003/078 413. In step a₁, a reducing agent such as LiAlH₄ or LiBH₄ is used. In step b₁, PCl₅ is used as chlorinating agent. Finally, in step c₁, potassium phthalimide and then hydrazine hydrate are reacted to prepare the compound of formula (II).

Where appropriate, a compound of formula (II) in which R₁ represents a hydrogen atom may be converted to a compound of formula (II) in which R₁ is a (C₁-C₄)alkyl by using methods known to those skilled in the art, for instance reaction with an alkylating agent, reductive amination with an aldehyde in reductive medium, or acylation with an acid chloride followed by reduction.

Preferentially, the oxazoles of formula (II) are prepared according to the following reaction scheme:

The compounds of formula (XII) are known or prepared via known methods, for example the methods described in International patent application WO 2003/007 887. In step a₂, the bromination may be performed, for example, via the action of bromine in a solvent such as benzene or dichloromethane or via the action of trimethylphenylammonium tribromide in tetrahydrofuran. In step b₂, a phthalimide derivative is reacted: the cesium salt of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid. The compound of formula (XV) obtained as an intermediate is treated in step c₂ with ammonium acetate to form the oxazole derivative of formula (XVI). In step d₂, the action of hydrazine allows the compound of formula (II) to be prepared.

Preferentially, the thiazoles of formula (II) are prepared according to the following reaction scheme:

In step a₃, the formation of the thiazole is obtained via the action of ethyl amino(thioxo)acetate on a compound of formula (XIII). The process is then performed as described above for Scheme 1.

The examples that follow describe the preparation of certain compounds in accordance with the invention. The examples are not limiting, and serve merely to illustrate the present invention. In the Preparations and the Examples, the following abbreviations are used:

-   -   DMF: N,N-dimethylformamide     -   THF: tetrahydrofuran     -   DCM: dichloromethane     -   MeOH: methanol     -   TFA: trifluoroacetic acid     -   AcOH: acetic acid     -   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene     -   DCC: 1,3-dicyclohexylcarbodiimide     -   DIPEA: diisopropylethylamine     -   BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium         hexafluorophosphate     -   PyBOP: benzotriazol-1-yloxytris(pyrrolidino)phosphonium         hexafluorophosphate     -   TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium         tetrafluoroborate     -   rt: room temperature     -   HPLC: high-performance liquid chromatography.

The compounds according to the invention are analyzed by LC/UV/MS coupling (liquid chromatography/UV detection/mass spectrometry). The molecular peaks (MH⁺) and the retention time (t) in minutes are measured.

Conditions MS2

An XTerra MS C18 column of 2.1×30 mm, 3.5 μm is used, at 30° C., flow rate 0.8 ml/minute.

The eluent is composed as follows:

-   -   solvent A: 0.025% trifluoroacetic acid (TFA) in water;     -   solvent B: 0.025% TFA in acetonitrile.

Gradient: Time (min) % A % B 0 100 0 2 0 100 2.7 0 100 2.75 100 0

The UV detection is performed with a diode array detector between 210 and 400 nm and the mass detection is performed in positive ESI chemical ionization mode.

Conditions MS5

An XTerra MS C18 column of 2.1×30 mm, 3.5 μm is used, flow rate 1 ml/minute.

The eluent is composed as follows:

-   -   Solvent A: 0.025% TFA in water,     -   Solvent B: 0.025% TFA in acetonitrile.

Gradient: Time (min) % A % B 0 100 0 2 0 100 2.7 0 100 2.75 100 0

The UV detection is performed with a diode array detector between 210 and 400 nm and the mass detection is performed in positive ESI mode.

Conditions MS4

A Tosohaas TSK gel Super ODS column of 4.6×50 mm, 2 μm is used, flow rate 2.75 ml/minute.

The eluent is composed as follows:

-   -   Solvent A: 0.05% TFA in water;     -   Solvent B: 0.05% TFA in acetonitrile.

Gradient: Time (min) % A % B 0 100 0 2 0 100 2.7 0 100 2.75 100 0

The UV detection is performed with a diode array detector between 210 and 400 nm and the mass detection is performed in positive ESI chemical ionization mode.

Conditions A

A Symmetry C18 column of 2.1×50 mm, 3.5 μm is used, at 30° C., flow rate 0.4 ml/minute.

The eluent is composed as follows:

-   -   Solvent A: 0.005% trifluoroacetic acid (TFA) in water at pH         3.15;     -   Solvent B: 0.005% TFA in acetonitrile.

Gradient: Time (min) % A % B 0 100 0 10 10 90 15 10 90 16 100 0 20 100 0

The UV detection is performed at λ220 nm and the mass detection is performed in positive ESI chemical ionization mode.

PREPARATIONS

1. Preparation of the compounds of formula (II) with Y═O

Preparation 1.1

1-(4-(2-chlorophenyl)-5-(4-chlorophenyl)-1,3-oxazol-2-yl)methananamine A) 2-bromo-1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone

29.54 g of phenyltrimethylammonium tribromide are added to a solution of 20.83 g of 1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone in THF. The homogeneous solution is stirred at room temperature for 1 hour 15 minutes. The reaction medium is filtered and concentrated to dryness. The crude reaction product is taken up in dichloromethane and washed successively with water, with aqueous Na₂CO₃ solution and then with water. The organic phase is dried over Na₂SO₄, filtered and concentrated to dryness by distilling off the solvent under reduced pressure. The product is obtained in the form of an oil that crystallizes slowly. The crystals are washed with a minimum amount of ethanol to give the expected product.

B) Cesium salt of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid

15 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid and 11.9 g of cesium carbonate are dissolved in an MeOH-H₂O mixture (10/1, v/v). The mixture is stirred for one hour at room temperature. The reaction medium is concentrated to dryness, taken up in acetone and evaporated to dryness (3 times). The crude product is then recrystallized from acetone. After filtering off the crystals and washing with ice-cold acetone, the expected product is obtained in a yield of 97%.

C) 2-((4-(2-chlorophenyl)-5-(4-chlorophenyl)-1,3-oxazol-2-yl)methyl-1H-isoindole-1,3-(2H)-dione

40.9 g of the cesium salt prepared in step B are added by spatula to a solution of 24.6 g of the bromo ketone obtained in step A, in DMF (300 ml). The mixture is stirred at room temperature for 48 hours. The resulting mixture is extracted with DCM/NaHCO₃ (1M). The mixture is filtered. The organic phase is dried over Na₂SO₄, filtered and evaporated to dryness, and the precipitate is then washed with water and rinsed with ether. The solids obtained from the organic phase and from the precipitate are combined, and the mixture is used in its present form in the following step.

8.8 g of the intermediate thus obtained are dissolved in 70 ml of acetic acid and 7.3 g of ammonium acetate are then added. The mixture is stirred at the reflux temperature of the solvent for 7 hours. The homogeneous mixture is then cooled to room temperature, leading to the formation of a precipitate. The mixture is filtered. On the one hand, the filtrate is dried over Na₂SO₄, filtered and evaporated to dryness. On the other hand, the precipitate is rinsed with ether. The products obtained are combined to give the expected compound.

D) 1-(4-(2-chlorophenyl)-5-(4-chlorophenyl)-1,3-oxazol-2-yl)methanamine

5.74 g of the phthalimide derivative obtained in the preceding step are dissolved in ethanol (200 ml) and fully dissolved at 50° C. 2.48 ml of hydrazine monohydrate are added and the mixture is maintained at the reflux temperature of the solvent for 4 hours, and the reaction medium is then cooled to room temperature. The mixture is filtered and the precipitate is rinsed with ethanol. The filtrate is concentrated and then taken up in ether. The second precipitate is again filtered off and rinsed with ether. The filtrate is washed with aqueous 10% KOH solution. The organic phase is dried over Na₂SO₄, filtered and concentrated to dryness. The expected product is obtained in the form of a yellowish solid.

Other intermediates of formula (II) with Y═O were prepared according to the procedure described below.

TABLE 1

Characterization Preparation No R3 R4 (conditions) Preparation 1.1

MH⁺ = 318.9t = 6.65(A) Preparation 1.2

MH⁺ = 352.9t = 7.15(A) Preparation 1.3

MH⁺ = 352.9t = 7.15(A) Preparation 1.4

MH⁺ = 348.9t = 6.76(A)

2. Preparations of the compounds of formula (II) with Y═S

Preparation 2.1

1-(4-(4-chlorophenyl)-5-(2,4-dichorophenyl)-1,3-thiazol-2-yl)methanamine A) 2-bromo-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)ethanone

2.5 ml of bromine are added dropwise to a solution of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)ethanone in dichloromethane (200 ml). The mixture is stirred for 4 hours at room temperature. The reaction medium is washed with water, with saturated aqueous NaHCO₃ solution and then with aqueous NH₄Cl solution. The organic phase is dried over Na₂SO₄, filtered and evaporated to dryness. The expected product is precipitated from pentane (yield=94%).

B) ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1,3-thiazole-2-carboxylate

17 g of the derivative obtained in the preceding step and 9 g of ethyl amino(thioxo)acetate are suspended in 10 ml of ethanol. The mixture is homogenized after 30 minutes at 50° C. Heating is continued for 6 hours at 50° C. The reaction medium is stirred at room temperature for 20 hours. The precipitate is then filtered off and washed with ethanol. The expected product is obtained in the form of a solid (yield=62.4%).

C) (4-(4-chlorophenyl)-5-(2,4-dicholorophenyl)-1,3-thiazol-2-yl)methanol

3.1 g of the compound obtained in the preceding step are dissolved in anhydrous THF and cooled to 0° C. 222 mg of LiAIH4 are added portionwise. After stirring for 1 hour 30 minutes at 0° C. under an inert atmosphere, the reaction medium is neutralized at 0° C. by successive addition of 222 μl of water and 222 μl of NaOH solution (4N), with stirring for 30 minutes, followed by addition of 222 μl of water. The mixture is filtered through Celite®. The filtrate is evaporated to dryness to give the expected product in crude form (yield=90%).

D) 2-chloromethyl-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1,3-thiazole

7 g of the alcohol derivative obtained in the preceding step are dissolved in 300 ml of DCM and cooled to 0° C. under an inert atmosphere. 3.95 g of PCl₅ are added portionwise over 10 minutes. After stirring for 15 minutes at 0° C., the stirring is continued overnight at room temperature. The reaction medium is poured into a 5% NaCL/ice mixture. The mixture is extracted with DCM. The combined organic phases are dried over Na₂SO₄, filtered and evaporated to dryness. The expected product is obtained in crude form (yield=92%).

E) 2-((4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1,3-thiazol-2-yl)methyl)-1H-isoindole-1,3-(2H)-dione

13.5 g of the chloro derivative obtained in the proceeding step are dissolved in anhydrous DMF. 9.4 g of potassium 1,3-dioxo-1,3-dihydroisoindol-2-ide are added and the mixture is heated at 65° C. for 20 hours. The heterogeneous medium is then filtered and the precipitate is rinsed with ether. The filtrate is evaporated to dryness. On the one hand, the precipitate is washed with water, with NaOH solution (0.2 M) and then with water (yield=54%). On the other hand, the residue is taken up in DCM and successively washed with aqueous NaOH solution (0.2 M) and with saturated NaCl solution. The organic phase is dried over Na₂SO₄, filtered and evaporated to dryness (yield=37%).

The two fractions are combined to give the expected product.

F) 1-(4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1,3-thiazol-2-yl)methanamine

9.5 g of the phthalimide derivative obtained in the preceding step are suspended in ethanol (300 ml), followed by addition of hydrazine hydrate (1.52 ml). The mixture is heated at the reflux temperature of the solvent for 4 hours. The reaction medium is cooled to room temperature. The heterogeneous medium is filtered. The filtrate is concentrated to dryness and taken up in ether. The medium, which has once again become heterogeneous, is filtered. The filtrate is washed successively with aqueous NaOH solution (0.2 M, 3 X) and then with water. The organic phase is dried over Na₂SO₄, filtered and evaporated to dryness to give the expected product (yield=67%).

Other intermediates of formula (II) with Y═S were prepared according to the procedure described above.

TABLE II

Characterization Preparation No. R3 R4 (conditions) Preparation 2.1

MH⁺ = 368.8t = 7.18(A) Preparation 2.2

MH⁺ = 368.8t = 7.30(A)

EXAMPLE 1

The compounds of formula (I) in which —X—═—CO— are prepared by combinatorial chemistry according to the process described below:

The carboxylic acids of formula (III) are dissolved in DMF to a concentration of 0.25 M in the presence of 3 equivalents of DIPEA. 120 μl of these solutions are placed in each 2 ml well and 120 μl of a solution of TBTU in DMF at a concentration of 0.25 M are added. 300 μl of a solution containing the methylamine of formula (II) in DMF at a concentration of 0.1 M and 3 equivalents of DIPEA are added to each well. The plates are shaken at rt for 16 hours and then evaporated. The products formed in each well are dissolved in 500 μl of EtOAc, 400 μl of 0.1 M Na₂CO₃ are then added and the plates are shaken. After separation of the phases by settling, 430 μl of aqueous phase are discarded, 300 μl of 5% NaCl are then added and the plates are shaken. 350 μl of aqueous phase are then discarded, 20 μl are taken for analysis by LC/UV/MS and the rest is evaporated under vacuum to obtain the expected compounds.

EXAMPLE 2

The compounds of formula (I) in which —X—═—CONH— are prepared by combinatorial chemistry according to the process described below:

The compounds of formula (II) are dissolved in DMF to a concentration of 0.1 M in the presence of 3 equivalents of DIPEA. 300 μl of these solutions are placed in each 2 ml well and 120 μl of a solution containing the isocyanate compound of formula (VIII) in THF at a concentration of 0.25 M are added. The plates are shaken at rt for 16 hours. The products formed in each well are dissolved by adding 500 μl of EtOAc, 400 μl of 0.1 M Na₂CO₃ are added, and the plates are shaken. After separation of the phases by settling, 430 μl of aqueous phase are discarded, 300 μl of 5% NaCl are added and the plates are shaken. After separation of the phases by settling, 350 μl of aqueous phase are discarded, 20 μl are taken for analysis by LC/UV/MS and the rest is evaporated under vacuum to obtain the expected compounds.

EXAMPLE 3

The compounds of formula (I) in which —X—═—SO₂— are prepared by combinatorial chemistry according to the process described below:

The compounds of formula (II) are dissolved in DMF to a concentration of 0.1 M in the presence of 3 equivalents of DIPEA. 300 μl of these solutions are added to each 2 ml well and 120 μl of a solution containing the corresponding sulfonyl chloride of formula (IV) in THF at a concentration of 0.25 M are added. The plates are shaken at rt for 16 hours and then evaporated. The products formed in each well are dissolved by adding 500 μl of EtOAc, 400 μl of 0.1 M Na₂CO₃ are added and the plates are shaken. After separation of the phases by settling, 430 μl of aqueous phase are discarded, 300 μl of 5% NaCl are added and the plates are shaken. After separation of the phases by settling, 350 μl of aqueous phase are discarded, 20 μl of taken for analysis by LC/UV/MS and the rest is evaporated under vacuum to obtain the expected compounds.

The tables that follow illustrate the chemical structures and the physical properties of a number of compounds according to the invention. In these tables, Me, Et, nPr and tBu illustrate, respectively, methyl, ethyl, n-propyl and tert-butyl groups.

TABLE III

Compound Characterization No. X R₂ R₃ R₄ Conditions 1 —CO—

MH⁺ = 541.4t = 2.07MS 2 2 —CO—

MH⁺ = 556.9t = 2.11MS 5 3 —CO—

MH⁺ = 561.5t = 2.07MS 2 4 —CO—

MH⁺ = 560.9t = 2.50MS 5 5 —SO₂—

MH⁺ = 517.8t = 2.06MS 5 6 —CO—

MH⁺ = 479.5t = 2.09MS 2

TABLE IV

Compound Characterization No. X R₂ R₃ R₄ Conditions 7 —CO—

MH⁺ = 577.5t = 2.10MS 2 8 —CO—

MH⁺ = 495.6t = 2.14MS 2 9 —CO—

MH⁺ = 548.8t = 2.58MS 5 10 —SO₂—

MH⁺ = 523.5t = 1.99MS 2 11 —SO₂—

MH⁺ = 537.5t = 2.07MS 2 12 —CO—

MH⁺ = 569.6t = 2.24MS 2 13 —SO₂—

MH⁺ = 545.4t = 2.01MS 2 14 —CSNH—

MH⁺ = 571.8t = 2.33MS 4 15 —SO₂—

MH⁺ = 527.4t = 1.98MS 2 16 —SO₂—

MH⁺ = 581.4t = 2.08MS 2 17 —CO—

MH⁺ = 565.5t = 2.17MS 2 18 —SO₂—

MH⁺ = 577.3t = 2.09MS 2 19 —SO₂—

MH⁺ = 543.4t = 2.03MS 2 20 —CO—

MH⁺ = 565.5t = 2.15MS 2 21 —CONH—

MH⁺ = 519.9t = 2.16MS 4 22 —CO—

MH⁺ = 467.0t = 2.20MS 4 23 —SO₂—

MH⁺ = 526.8t = 2.24MS 4 24 —CO—

MH⁺ = 569.0t = 2.38MS 4 25 —SO₂—

MH⁺ = 544.8t = 2.26MS 4 26 —SO₂—

MH⁺ = 542.8t = 2.27MS 4 27 —SO₂—

MH⁺ = 576.8t = 2.28MS 4

The compounds of formula (I) show very good in vitro affinity (IC₅₀≦5×10⁻⁷ M) for the CB, cannabinoid receptors, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-244).

The antagonist nature of the compounds of formula (I) was demonstrated by means of the results obtained in models of inhibition of adenylate cyclase, as described in M. Bouaboula et al., J. Biol. Chem., 1995, 270, 13973-13980, M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1996, 278, 871-878 and M. Bouaboula et al., J. Biol. Chem., 1997, 272, 22330-22339.

The toxicity of the compounds of formula (I) is compatible with their use as medicaments.

Thus, according to another of its aspects, a subject of the invention is medicaments for human and veterinary medicine, comprising a compound of formula (I), or alternatively a solvate or a hydrate of the compound of formula (I).

Thus, the compounds according to the invention may be used in the treatment or prevention of diseases involving the CB₁ cannabinoid receptors in man or animals.

For example, and in a non-limiting manner, the compounds of formula (I) are useful as psychotropic medicaments, especially for treating psychiatric disorders including anxiety, depression, mood disorders, insomnia, delirium disorders, obsessive disorders, psychoses in general, schizophrenia, attention and hyperactivity disorders (AHD) in hyperkinetic children (MBD), and also for the treatment of disorders associated with the use of psychotropic substances, especially in the case of a substance abuse and/or dependency on a substance, including alcohol dependency and nicotine dependency.

The compounds of formula (I) according to the invention may be used as medicaments for treating migraine, stress, diseases of psychosomatic origin, panic attacks, epilepsy, motor disorders, in particular dyskinesia or Parkinson's disease, trembling and dystonia.

The compounds of formula (I) according to the invention may also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementia and Alzheimer's disease, and also in the treatment of attention or consciousness disorders. Furthermore, the compounds of formula (I) may be useful as neuroprotective agents, in the treatment of ischaemia, cranial trauma and the treatment of acute or chronic neurodegenerative diseases: including chorea, Huntington's chorea and Tourrette's syndrome.

The compounds of formula (I) according to the invention may be used as medicaments in the treatment of pain: neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin.

The compounds of formula (I) according to the invention may be used as medicaments in human or veterinary medicine, in the treatment of appetite disorders, appetence disorders (for sugars, carbohydrates, drugs, alcohol or any appetizing substance) and/or eating behavioral disorders, especially for the treatment of obesity or bulimia and also for the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidemias and metabolic syndrome. Thus, the compounds of formula (I) according to the invention are useful in the treatment of obesity and the risks associated with obesity, especially the cardiovascular risks.

Furthermore, the compounds of formula (I) according to the invention may be used as medicaments in the treatment of gastrointestinal disorders, diarrhea disorders, ulcers, vomiting, bladder and urinary disorders, disorders of endocrine origin, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic liver cirrhosis, hepatic steatosis, steatohepatitis, asthma, Raynaud's syndrome, glaucoma, fertility disorders, premature interruption of pregnancy, premature birth, inflammatory phenomena, immune system diseases, in particular autoimmune diseases and neuroinflammatory diseases such as rheumatoid arthritis, reactional arthritis, diseases resulting in demyelinization, multiple sclerosis, infectious and viral diseases such as encephalitis, strokes, and also as medicaments for anticancer chemotherapy, for the treatment of Guillain-Barré syndrome and for the treatment of bone diseases and osteoporosis.

According to the present invention, the compounds of formula (I) are most particularly useful for treating psychotic disorders, in particular schizophrenia, attention and hyperactivity disorders (AHD) in hyperkinetic children; appetite and obesity disorders; memory and cognitive deficits; alcohol dependency, nicotine dependency, i.e. weaning from alcohol and weaning from tobacco.

More particularly, the compounds of formula (I) according to the present invention are useful in the treatment and prevention of appetite disorders, metabolic disorders, gastrointestinal disorders, inflammatory phenomena, immune system diseases, psychotic disorders, alcohol dependency and nicotine dependency.

According to one of its aspects, the present invention relates to the use of a compound of formula (I), and solvates or hydrates thereof for treating the disorders and diseases indicated above.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, a solvate or a hydrate of the said compound, and also at least one pharmaceutically acceptable excipient.

The said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or the possible solvate or hydrate thereof, may be administered in a unit form of administration, as a mixture with standard pharmaceutical excipients, to man and animals for the prophylaxis or treatment of the above disorders or diseases.

The appropriate unit forms of administration include oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention may be used in creams, gels, pomades or lotions.

By way of example, a unit form of administration of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg  Sodium croscarmellose  6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate  3.0 mg

Via the oral route, the dose of active principle administered per day may be from 0.01 to 100 mg/kg in one or more dosage intakes, preferentially 0.02 to 50 mg/kg.

There may be particular cases in which higher or lower dosages are appropriate; such dosages do not depart from the context of the invention. According to the usual practice, the dosage that is appropriate to each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.

According to another of its aspects, the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration to a patient of an effective dose of a compound according to the invention, or a hydrate or solvate.

Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof. 

1. A compound of formula (I):

wherein: X represents a group

Y represents an oxygen atom or a sulfur atom; R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group; R₂ represents: a (C₁-C₇)alkyl; a C₃-C₁₂ non-aromatic carbocyclic radical, which is unsubstituted or substituted one or more times with a (C₁-C₄)alkyl; a methyl substituted with a C₃-C₁₂ non-aromatic carbocyclic radical that is unsubstituted or substituted one or more times on the carbocycle with a (C₁-C₄)alkyl; a phenyl, which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom, a (C₁-C₄)alkyl, a hydroxyl, a (C₁-C₄)alkoxy, a cyano, a trifluoromethyl group, a trifluoromethoxy group; or from a phenyl, phenoxy, pyrrolyl, imidazolyl, pyridyl or pyrazolyl radical, the said radicals being unsubstituted or substituted one or more times with a (C₁-C₄)alkyl; a phenoxymethyl, which is unsubstituted on the methyl or substituted on the methyl with one or two (C₁-C₄)alkyl groups, and unsubstituted on the phenyl or substituted on the phenyl with one or more substituents independently chosen from a halogen atom, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a trifluoromethyl group and a trifluoromethoxy group; a benzyl, which is unsubstituted or substituted one or more times on the phenyl with substituents independently chosen from a halogen atom, a cyano, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a trifluoromethyl group and a trifluoromethoxy group; or α-substituted with one or two identical or different groups chosen from a (C₁-C₄)alkyl and a (C₃-C₇)cycloalkyl; a benzhydryl or a benzhydrylmethyl group; a 1,2,3,4-tetrahydro-2-naphthyl, which is unsubstituted or substituted one or more times with a (C₁-C₄)alkyl; a pyrrolyl, imidazolyl, pyridyl, pyrazolyl, furyl or thienyl radical, the said radicals being unsubstituted or substituted with one or more substituents independently chosen from a halogen atom, a (C₁-C₄)alkyl and a trifluoromethyl group; a 2-indolyl, which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom and a (C₁-C₄)alkyl; a benzofuryl, which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom and a (C₁-C₄)alkyl group; R₃ represents a phenyl, which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a trifluoromethyl or trifluoromethoxy group and a group S(O)_(n)Alk; R₄ represents a phenyl, which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a trifluoromethyl or trifluoromethoxy group, and a group S(O)_(n)Alk; R₅ represents a hydrogen atom or a (C₁-C₄)alkyl; n represents 0, 1 or 2; Alk represents a (C₁-C₄)alkyl; and with the proviso that when X represents a group —CO— or —CONR₅—, R₂ is other than: a C₄-C₇ non-aromatic carbocyclic radical, which is unsubstituted or substituted one or more times with a (C₁-C₄)alkyl; a phenyl, which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom, a (C₁-C₄)alkyl, a hydroxyl, a (C₁-C₄)alkoxy, a cyano and a trifluoromethyl group; or from a 1-pyrrolyl or 1-pyrazoyl radical; a 1,2,3,4-tetrahydronaphthyl, which is unsubstituted or substituted one or more times with a (C₁-C₄)alkyl; a pyrrolyl, imidazolyl, pyridyl, pyrazolyl, furyl or thienyl radical, the said radicals being unsubstituted or substituted with one or more substituents independently chosen from a halogen atom, a (C₁-C₄)alkyl and a trifluoromethyl group; an indolyl, which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom and a (C₁-C₄)alkyl; and a benzofuryl, which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom and a (C₁-C₄)alkyl; or a salt thereof, or a hydrate or a solvate thereof.
 2. The compound of formula (I) according to claim 1, wherein —Y— represents an oxygen atom; or a salt thereof, or a hydrate or a solvate thereof
 3. The compound of formula (I) according to claim 1, wherein —Y— represents a sulfur atom; or a salt thereof, or a hydrate or a solvate thereof.
 4. The compound of formula (I) according to claim 1, wherein —X— represents a group —CO—; or a salt thereof, or a hydrate or a solvate thereof.
 5. The compound of formula (I) according to claim 1, wherein —X— represents a group —SO₂—; or a salt thereof, or a hydrate or a solvate thereof.
 6. The compound of formula (I) according to claim 1, wherein —X— represents a group —CON(R₅)—; or a salt thereof, or a hydrate or a solvate thereof.
 7. The compound of formula (I) according to claim 1, wherein —X— represents a group —CSN(R₅)—, and wherein R₅ is as defined in claim 1; or a salt thereof, or a hydrate or a solvate thereof.
 8. A process for preparing a compound of formula (I), comprising: reacting a compound of formula (II):

wherein Y, R₁, R₃ and R₄ are as defined in claim 1, either with an acid of formula (III) or a functional derivative thereof: HOOC—R₂   (III) wherein R₂ is as defined in claim 1, to form a compound of formula (I) in which —X— represents a group —CO—; or with a sulfonyl halide of formula (IV): Hal-SO₂—R₂   (IV) wherein R₂ is as defined in claim 1 and Hal represents a halogen atom, to form a compound of formula (I) in which —X— represents a group —SO₂—; or with a haloformate of formula (V): HalCOOAr   (V) wherein Hal represents a halogen atom and Ar represents a phenyl or a 4-nitrophenyl, to obtain an intermediate compound of formula (VI):

wherein Y, R₁, R₃ and R₄ are as defined in claim 1, which is then reacted with an amine of formula (VII): HN(R₅)R₂   (VII) wherein R₂ and R₅ are as defined in claim 1, to form a compound of formula (I) in which —X— represents a group —CON(R₅)—; or with an isothiocyanate of formula (VIII), R₂N═C═S (VIII), to form a compound of formula (I) in which —X— represents a group —CSNH—.
 9. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof in combination with at least one pharmaceutically acceptable excipient.
 10. A pharmaceutical composition comprising a compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof in combination with at least one pharmaceutically acceptable excipient.
 11. A pharmaceutical composition comprising a compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof in combination with at least one pharmaceutically acceptable excipient.
 12. A pharmaceutical composition comprising a compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof in combination with at least one pharmaceutically acceptable excipient.
 13. A pharmaceutical composition comprising a compound of formula (I) according to claim 5 or a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof in combination with at least one pharmaceutically acceptable excipient.
 14. A pharmaceutical composition comprising a compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof in combination with at least one pharmaceutically acceptable excipient.
 15. A pharmaceutical composition comprising a compound of formula (I) according to claim 7 or a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof in combination with at least one pharmaceutically acceptable excipient.
 16. A method for treating a disease selected from the group consisting of appetite disorder, metabolic disorder, gastrointestinal disorder, inflammatory phenomena, immune system disease, psychotic disorder, alcohol dependency and nicotine dependency comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim
 1. 17. A method for treating a disease selected from the group consisting of appetite disorder, metabolic disorder, gastrointestinal disorder, inflammatory phenomena, immune system disease, psychotic disorder, alcohol dependency and nicotine dependency comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim
 2. 18. A method for treating a disease selected from the group consisting of appetite disorder, metabolic disorder, gastrointestinal disorder, inflammatory phenomena, immune system disease, psychotic disorder, alcohol dependency and nicotine dependency comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim
 3. 19. A method for treating a disease selected from the group consisting of appetite disorder, metabolic disorder, gastrointestinal disorder, inflammatory phenomena, immune system disease, psychotic disorder, alcohol dependency and nicotine dependency comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim
 4. 20. A method for treating a disease selected from the group consisting of appetite disorder, metabolic disorder, gastrointestinal disorder, inflammatory phenomena, immune system disease, psychotic disorder, alcohol dependency and nicotine dependency comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim
 5. 21. A method for treating a disease selected from the group consisting of appetite disorder, metabolic disorder, gastrointestinal disorder, inflammatory phenomena, immune system disease, psychotic disorder, alcohol dependency and nicotine dependency comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim
 6. 22. A method for treating a disease selected from the group consisting of appetite disorder, metabolic disorder, gastrointestinal disorder, inflammatory phenomena, immune system disease, psychotic disorder, alcohol dependency and nicotine dependency comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim
 7. 23. The method according to claim 16, wherein the disease is appetite disorder.
 24. The method according to claim 16, wherein the disease is metabolic disorder.
 25. The method according to claim 16, wherein the disease is gastrointestinal disorder.
 26. The method according to claim 16, wherein the disease is inflammatory phenomena.
 27. The method according to claim 16, wherein the disease is immune system disease.
 28. The method according to claim 16, wherein the disease is psychotic disorder.
 29. The method according to claim 16, wherein the disease is alcohol or nicotine dependency. 